This Application is a 371 of PCT/EP01/11575 Oct. 08, 2001.
The present invention relates to a process of synthesis of R(+)xcex1-lipoic acid through the formation of diastereoisomeric salts of racemic thioctic acid with optic isomers of xcex1-methylbenzylamine.
It is well known from the state of the art about the process of resolution of racemic mixtures, or racemates, i.e. the splitting of a racemate into the enantiomers constituting it. The racemate is first transformed into a mixture of diastereoisomers by reaction with an optically active substance. The diastereoisomers thus obtained, characterized by different physical properties among which solubility, are generally separated by fractioned crystallization. The enantiomers of the starting racemic mixture are obtained from said separated diastereoisomers by simple chemical reactions of separation of said diastereoisomers.
U.S. Pat. No. 5,281,722 describes diastereoisomeric salts obtained from pure enatiomers of xcex1-lipoic acid by reaction with optic isomers of xcex1-methylbenzylamine. The state of the art describes methods for the preparation of said diastereoisomeric salts and their use as intermediate products in the resolution of a racemic mixture of thioctic acid in both optically active enantiomeric forms R(+) and S(xe2x88x92) of xcex1-lipoic acid. The process of resolution of racemic thioctic acid has a low yield, in particular for the separation of the R(+)xcex1-lipoic enantiomer (see Examples 7 and 8 of U.S. Pat. No. 5,281,722).
As a matter of fact, the purification processes described at the state of the art for diastereoisomeric salts have a low enantiomeric enrichment of the salt of the R(+)xcex1-lipoic isomer. This is further confirmed by the high number of re-crystallizations carried out on diastereoisomeric salts before the scission reaction with acids.
Tests carried out by the Applicant show that the scission of the purified diastereoisomeric salts by addition of inorganic acids, for instance mineral acids such as 1N hydrochloric acid, to obtain the two separated optically active enantiomeric forms R(+) and S(xe2x88x92) of xcex1-lipoic acid, as described in U.S. Pat. No. 5,281,722, results in low-quality enantiomers of xcex1-lipoic acid presence of polymers).
The state of the art described the use of diastereoisomeric salts obtained from the enantiomers of xcex1-lipoic acid by means of reaction with optically active bases in order to separate the isomers R(+) and S(xe2x88x92) of xcex1-lipoic acid. However, the processes described at the state of the art, as verified by the Applicant, are characterized by complex and long methods for purifying intermediate diastereoisomeric salts, with low yields of resolution of racemates as well as an unsatisfying quality of the optic isomers thus obtained.
There was therefore a need for a process of synthesis of the optic isomer R(+) of xcex1-lipoic acid starting from racemic thioctic acid with a higher resolution yield. Said process should consist of few stages of purification of intermediate diastereoisomeric salts, so as to obtain a R(+)xcex1-lipoic acid of higher quality.
It has now been found a new process of synthesis of R(+)xcex1-lipoic acid through the resolution of racemic thioctic acid, said process to overcoming the disadvantages characterizing the processes at the state of the art, such as complexity, low yield and low quality of the optic isomers obtained.
Quite unexpectedly and surprisingly, the Applicant has found a new process of synthesis of R(+)xcex1-lipoic acid by reacting racemic thioctic acid with the optically active base R(+)xcex1-methylbenzylamine, thus obtaining the diastereoisomeric salt of R(+)xcex1-lipoic acid-R(+)xcex1-methylbenzylamine, followed by its purification by fractioned crystallization and scission of the salt with acids.
An object of the present invention is therefore a process of synthesis of R(+)xcex1-lipoic acid comprising the following stages:
a) salifying of racemic thioctic acid with R(+)xcex1-methylbenzylamine (FEA), wherein the molar ratio FEA/racemic thioctic acid is between 0.45 and 0.70;
b) separation by filtration of the crystallized diastereoisomeric salt of R(+)xcex1-lipoic acid-R(+)xcex1-methylbenzylamine;
c) purification by re-crystallization of the diastereoisomeric salt of R(+)xcex1-lipoic acid-R(+)xcex1-methylbenzylamine, wherein the re-crystallization solvent consists of a mixture of non-polar/polar solvents, the polar solvent being maximum 20% by volume of the mixture, and the temperature of dissolution of the salt is between 50 and 75xc2x0 C.;
d) separation of the diastereoisomeric salt to obtain R(+)xcex1-lipoic acid by reaction of said salt with acids selected from the group consisting of aliphatic hydroxy-carboxylic acids having 3 to 6 carbon atoms and aqueous phosphoric acid with a dilution between 2 and 10% by weight.
According to the process of synthesis of the present invention, in the salifying stage a) the molar ratio FEA/racemic thioctic acid is preferably between 0.55 and 0.65, still more preferably between 0.57 and 0.63. The salifying in stage a) is carried out at atmospheric pressure in an organic solvent, preferably toluene, at a temperature between 30 and 60xc2x0 C., preferably between 35 and 40xc2x0 C. The concentration of the racemic thioctic acid in salifying stage a) is between 5 and 40% w/v, preferably between 8 and 20% w/v, still more preferably between 9 and 13% w/v of solvent.
Stage b), i.e. separation by filtration of the diastereoisomeric salt, takes place at a temperature of 10 to 30xc2x0 C., preferably at 25xc2x0 C.
In stage c), i.e. purification by re-crystallization of the diastereoisomeric salts of R(+)xcex1-lipoic acid-R(+)xcex1-methylbenzylamine, the mixture of non-polar/polar solvents is preferably chosen between toluene/methanol and toluene/dimethylformamide (DMF). As far as the mixture toluene/methanol is concerned, the volume ratio of the solvents is between 80:20 and 99:1, preferably between 90:10 and 98.5:1.5, still more preferably between 91:9 and 98:2. As far as the mixture toluene/dimethylformamide (DMF) is concerned, the volume ratio of the solvents is between 70:30 and 85:15, preferably between 75:25 and 84:16, still more preferably 78:22 and 80:20. The concentration of the diastereoisomeric salt in purification stage c) is between 7 and 15% w/v, preferably between 9 and 14% w/v, still more preferably between 10 and 12% w/v of mixture of non-polar/polar solvents.
In stage c), i.e. purification of the diastereoisomeric salt, the dissolution of the latter, at a temperature preferably between 57 and 72xc2x0 C., still more preferably between 60 and 70xc2x0 C., is followed by the precipitation of the crystals of the salt of R(+)xcex1-lipoic acid-R(+)xcex1-methylbenzylamine by cooling at a temperature between 10 and 25xc2x0 C.
In stage d), i.e. separation of the diastereoisomeric salt, the preferred aqueous phosphoric acid has a dilution between 4 and 8% by weight, still more preferred is phosphoric acid diluted at 5% by weight. In stage d), i.e. separation of the diastereoisomeric salt, the preferred hydroxy-carboxylic acid is citric acid in an equimolar amount with respect to the diastereoisomeric salt.
The yield of the process of synthesis of R(+)xcex1-lipoic acid according to the present invention can be further increased through a stage dxe2x80x2) providing for the recycling of the mother liquors from stage b), i.e. re-crystallization of the diastereoisomeric salt, and from stage c), i.e. purification of said salt by re-crystallization. Said stage dxe2x80x2) of recycling of mother liquors comprises:
I. gathering of mother liquors from stages b) and c);
II. their treatment with acid aqueous solutions;
III. concentration to dryness of the organic phase by evaporation under vacuum, thus obtaining xcex1-lipoic acid with an excess of the enantiomer S(xe2x88x92);
IV. racemization of xcex1-lipoic acid with an excess of the enantiomer S(xe2x88x92) in an organic solvent having a boiling point above 200xc2x0 C. and selected from the group consisting of: linear or branched aliphatic C12-C20 hydrocarbons, aromatic C12-C20 hydrocarbons, C12-C20 arylalkyl hydrocarbons or their mixtures, wherein the concentration of xcex1-lipoic acid with an excess of the enantiomer S(xe2x88x92) is between 20% and 50% w/v of solvent, by heating at atmospheric pressure at a temperature between 170 and 210xc2x0 C. for less than 10 hours;
V. recycling of racemic xcex1-lipoic acid to reaction stage a).
In the stage of racemization of xcex1-lipoic acid according to the present invention the organic solvent is preferably a solvent with a boiling point above 220xc2x0 C., selected from the group consisting of mixtures of isomers of benzyltoluene (MARLOTHERM(copyright) LH), mixtures of partially hydrogenated terphenyls (DOWTHERM(copyright), SANTOTHERM(copyright) 66), mixtures of alkylbenzenes (SANTOTHERM(copyright) 55), mixtures of diphenyl (DIPHYL(copyright)) and mixtures of diphenyl oxide (DIPHYL(copyright) DT). Still more preferred as solvent in the stage of racemization of xcex1-lipoic acid is MARLOTHERM(copyright) LH, a mixture of isomers of benzyltoluene having a boiling point at atmospheric pressure between 278 and 282xc2x0 C. The concentration of xcex1-lipoic with an excess of the enantiomer S(xe2x88x92) in the racemization stage is preferably between 25% and 40% w/v, still more preferably between 30 and 35% w/v of solvent. The racemization temperature according to the present invention is preferably between 175 and 205xc2x0 C., still more preferably between 180 and 200xc2x0 C.
The following are some examples disclosing though not limiting the framework of the present invention.